Microinjections of D-Ala-2-met-enkephalin into the periaqueductal gray matter produced profound analgesia which persisted for 2 to 3 hours. Tolerance and addictive liability were also demonstrated for enkephalin. Intraventricular injections of D-Ala2-met-enkephalin, morphine and Beta-endorphin produced a biphasic effect on spontaneous motility--initial depression followed by excitation. The depression and excitation were found to be mediated by different brain structures. Naloxone, an opiate antagonist, was found to depress activity. Microionotophoretic applications of horseradish peroxidase to brainstem nuclei indicated that afferents to the raphe magnus originate from the periadqueductal gray matter and surrounding tegmentum. The adjacent reticular nuclei received afferents mainly from within or caudal to the pons-medulla. Foot-shock stress did not alter the released endogenous opiate ligands into monkey cerebrospinal fluid. BIBLIOGRAPHIC REFERENCES: Pert, C.B., Pert, A. and Tallman, J.F.: Isolation of a novel endogenous opiate analgesic from human blood. Proc. Natl. Acad. Sci. USA, 73: 2226-2230, 1977. Pert, A. and Sivit, C. A neuroanatomical focus for morphine and enkephalin-induced hypermotility. Nature, 265: 645-647, 1977.